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Complement Inhibitors Block Complement C3 Opsonization and Improve Targeting Selectivity of Nanoparticles in Blood.

ABSTRACT: Complement is one of the critical branches of innate immunity that determines the recognition of engineered nanoparticles by immune cells. Antibody-targeted iron oxide nanoparticles are a popular platform for magnetic separations, in vitro diagnostics, and molecular imaging. We used 60 nm cross-linked iron oxide nanoworms (CLIO NWs) modified with antibodies against Her2/neu and EpCAM, which are common markers of blood-borne cancer cells, to understand the role of complement in the selectivity of targeting of tumor cells in whole blood. CLIO NWs showed highly efficient targeting and magnetic isolation of tumor cells spiked in lepirudin-anticoagulated blood, but specificity was low due to high uptake by neutrophils, monocytes, and lymphocytes. Complement C3 opsonization in plasma was predominantly via the alternative pathway regardless of the presence of antibody, PEG, or fluorescent tag, but was higher for antibody-conjugated CLIO NWs. Addition of various soluble inhibitors of complement convertase (compstatin, soluble CD35, and soluble CD55) to whole human blood blocked up to 99% of the uptake of targeted CLIO NWs by leukocytes, which resulted in a more selective magnetic isolation of tumor cells. Using well-characterized nanomaterials, we demonstrate here that complement therapeutics can be used to improve targeting selectivity.

SUBMITTER: Gaikwad H

PROVIDER: S-EPMC7528420 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Nontuberculous mycobacteria (NTM), including Mycobacterium avium, are clinically important pathogens in cystic fibrosis (CF). The innate immune response to M. avium remains incompletely understood. We evaluated the role of complement opsonization in neutrophil-mediated killing of M. avium. Killing assays were performed using neutrophils from healthy donors (HDs) and persons with CF (pwCF). Clinical isolates of M. avium were opsonized with plasma from HDs or pwCF, which was intact or heat-treated to inactivate complement. HD neutrophils had killing activity against M. avium opsonized with intact HD plasma and killing was significantly reduced when M. avium was opsonized with heat-inactivated HD plasma. When opsonized with HD plasma, CF neutrophils had killing activity against M. avium that was not different than HD neutrophils. When opsonized with intact plasma from pwCF, HD neutrophil killing of M. avium was significantly reduced. Opsonization of M. avium with C3-depleted serum or IgM-depleted plasma resulted in significantly reduced killing. Plasma C3 levels were elevated in pwCF with NTM infection compared to pwCF without NTM infection. These studies demonstrate that human neutrophils efficiently kill M. avium when opsonized in the presence of plasma factors from HD that include C3 and IgM. Killing efficiency is significantly lower when the bacteria are opsonized with plasma from pwCF. This indicates a novel role for opsonization in neutrophil killing of M. avium and a deficiency in complement opsonization as a mechanism of impaired M. avium killing in CF. IMPORTANCE Mycobacterium avium is a member of a group of bacterial species termed nontuberculous mycobacteria (NTM) that cause lung disease in certain populations, including persons with cystic fibrosis (CF). NTM infections are challenging to diagnose and can be even more difficult to treat. This study investigated how the immune system responds to M. avium infection in CF. We found that neutrophils, the most abundant immune cell in the lungs in CF, can effectively kill M. avium in individuals both with and without CF. Another component of the immune response called the complement system is also required for this process. Levels of complement proteins are altered in persons with CF who have a history of NTM compared to those without a history of NTM infection. These results add to our understanding of how the immune system responds to M. avium, which can help pave the way toward better diagnostic and treatment strategies.

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Complement Inhibitors Block Complement C3 Opsonization and Improve Targeting Selectivity of Nanoparticles in Blood.

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